美国哈佛大学医学院等机构的研究人员分析了200多人的脑组织样本，包括tau蛋白相关神经退行性疾病 患者、致病因素不是tau蛋白的痴呆症患者以及健康人。利用蛋白质组分析和人工智能技术，研究人员 鉴定出了tau蛋白中与疾病相关的145个修饰位点和195个切割位点，识别出不同疾病对应的tau蛋白分子 特征等信息。 新华社北京2月9日电 美国研究团队近日在美国《细胞》杂志上发表论文说，他们绘制出了一类致病蛋 白质——病理性tau蛋白的全面图谱，确定了多种相关的神经退行性疾病中tau蛋白分子的独有特征。这 将有助于尽早诊断与这种蛋白质相关的神经退行性疾病，并开发药物。 作为一种主要存在于神经元中的蛋白质，tau蛋白在正常状态下对维持神经元的结构和功能起着重要作 用。如果tau蛋白分子折叠成错误的形状，会导致神经元死亡、智力受损乃至痴呆。氨基酸按照DNA （脱氧核糖核酸）编码连接形成蛋白质分子后，通常还要经过化学修饰和蛋白质剪切才能执行生理功 能。此前研究发现，不同的修饰和剪切方式决定了病理性tau蛋白的形状，影响它毒害神经元的方式及 疾病发病进程。 研究人员表示，迄今医学界已经发现了约20种与tau蛋白相关的神经退行性 ...

来源：科技日报 ◎ 科技日报记者 张佳星 神经退行性疾病的脑网络病变机制当前尚不明确，致使针对脑功能异常的治疗如"盲人摸象"，进展缓 慢。2月5日，《自然》杂志发表的一项成果首次清晰揭示了帕金森病的致病关键环路，针对该环路进行 精准靶向的磁刺激可以有效改善患者的症状，证明了该机制的重要临床意义。 "我们发现大脑的一个关键脑网络在帕金森病中发挥核心作用，这个网络是由大脑皮层功能区和脑深部 核团共同构成的大规模网络，我们称它为躯体认知环路。"论文通讯作者、昌平实验室领衔科学家刘河 生教授说，与健康人群相比，帕金森病患者的躯体认知环路表现出显著的过度连接。 团队发现，躯体认知环路的过度连接在多个帕金森病患者的独立数据集中均得到了重复验证，但并未出 现在肌张力障碍等其他疾病中。深度分析显示，现有有效治疗帕金森病的手段都是通过改善躯体认知环 路发挥作用，如深部脑刺激手术中的"有效刺激位点"区域与该关键网络相关。更强有力的证据在于，团 队在运动症状改善的患者大脑内观察到过度连接的下降，表明深部脑刺激是通过特异性下调这一环路的 异常连接而发挥治疗作用。 "我们的发现为靶向干预提供了精准'靶点'。"刘河生介绍，基于此发现，团 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 细胞衰老 （ Cellular senescence ） 通常被定义为一种细胞状态，其特征是在没有细胞死亡的情况下细胞周期永久性停滞。衰老细胞表现出几个典型的特征，包 括停止分裂状态、细胞形态改变、线粒体功能障碍、活性氧 （ROS） 水平升高、DNA 损伤和突变率增加以及衰老相关分泌表型 （SASP） 。 细胞衰老会影响人一生中的大脑健康和疾病；因此，研究人员正在努力识别包括大脑组织在内的各种人体组织中衰老细胞特有的基因和蛋白质表达模式。例如， 衰老在发育过程中发挥着重要作用，尤其是在诸如神经管闭合等对大脑结构正常形成至关重要的过程中。相反，在正常衰老过程中，大脑组织中衰老细胞的比例 逐渐增加。在病理学背景下， 细胞衰老 与年龄相关的 神经退行性疾病 有关，包括阿尔茨海默病 （AD） 和帕金森病 （PD） ，而在发育过程中，衰老通路的异 常激活或激活时机不当，可能在神经发育异常中发挥致病作用。因此，弄清楚衰老细胞如何在人的一生中影响大脑健康和疾病，至关重要。 2026 年 1 月 22 日， 西奈山伊坎医学院的研究人员在国际顶尖学术期刊 Cell 上发表了题为： Est ...

Core Insights - The research published by the team from Mount Sinai's Icahn School of Medicine establishes a direct link between cellular aging and brain structure, providing new perspectives on brain development, aging, and neurodegenerative diseases [1][3]. Group 1: Research Findings - Understanding brain structure is a core challenge in neuroscience, with its changes throughout life closely related to aging and neurodegenerative diseases such as Parkinson's and Alzheimer's [3]. - The study combines biopsy samples from the prefrontal cortex obtained during deep brain stimulation surgery with brain imaging data, allowing for simultaneous analysis of molecular features and brain structure in the same individual [3]. - A novel method was developed to identify aging cells in live human brain tissue, exploring the relationship between aging-related gene expression and brain structure [3][4]. Group 2: Key Discoveries - One significant finding is that the impact of cellular aging on brain structure varies by cell type and life stage; genes related to the aging of microglia are associated with larger brain volume, while those related to excitatory neurons are linked to reduced brain volume during aging [4]. - Aging-related characteristics of excitatory neurons are evident early in life, indicating that the aging process begins shortly after embryonic development [4]. - The study also detected signs of aging during developmental stages, suggesting that this process may play a critical role in early brain development [4].

Core Viewpoint - Neurodegenerative diseases, such as Alzheimer's and Parkinson's, affect 1 in every 12 people globally and currently lack curative methods. The core mechanism involves the loss of protein homeostasis and accumulation of protein aggregates in neurons as age increases [3]. Group 1: Research Findings - A study published by Stanford University in Nature reveals that the half-life of neuronal proteins in older brains is on average doubled compared to younger brains, indicating a significant decline in protein homeostasis with age [3]. - The research found that 54% of proteins in aging microglia show reduced degradation and/or accumulation with age, particularly synaptic proteins, which may lead to synaptic loss and cognitive decline [3][6]. Group 2: Protein Homeostasis and Aging - The brain's protein homeostasis, which maintains a balance between protein synthesis and degradation, deteriorates with age, leading to the accumulation of "protein waste" in neurons [6]. - The study highlights that the average half-life of neuronal proteins increases by approximately 100% from young to old age, meaning that older brains clear proteins at about half the rate of younger brains [10]. Group 3: Implications of Protein Accumulation - The research identified 1,726 neuronal proteins in the aging brain, with nearly half showing slowed degradation and/or forming aggregates, including risk gene products associated with neurodegenerative diseases [12]. - Notably, 54% of aggregated proteins exhibit decreased degradation rates with age, indicating that degradation defects directly contribute to protein accumulation, particularly affecting synaptic proteins [12]. Group 4: Role of Microglia - Microglia, the brain's immune cells, are responsible for clearing cellular debris and protein waste. The study found that aging neurons transfer proteins to microglia, which become overwhelmed as the amount of protein to process increases significantly in older mice [14]. - In aged microglia, the quantity of neuronal proteins is over ten times that found in younger mice, with more than half showing degradation defects and/or aggregation tendencies [14]. Group 5: Future Applications - The study not only uncovers new mechanisms of brain aging but also provides a powerful tool for studying protein dynamics. The BONCAT technology can be used to screen for drugs that promote protein degradation, offering new targets for treating age-related brain diseases [18]. - Future interventions may focus on enhancing the degradation capabilities of neurons or improving the clearance abilities of microglia to alleviate protein aggregation [18].

Core Findings - The study provides a detailed protein atlas of lysosomes in various brain cell types, identifying previously unannotated lysosomal proteins and revealing the diversity of lysosomal composition across different brain cell types [4][10][11] - SLC45A1, a neuron-specific lysosomal protein, is redefined as a lysosomal storage disorder (LSD) due to its mutation leading to significant lysosomal dysfunction [4][8][16] Lysosomal Function and Importance - Lysosomes are membrane-bound organelles responsible for degrading macromolecules and clearing damaged organelles, crucial for maintaining cellular homeostasis [6] - They play a key role in nutrient and energy sensing pathways, impacting cellular metabolism and are involved in various cellular functions such as membrane repair and programmed cell death [6] Research Methodology - The research utilized a LysoTag mouse model combined with cell-type specific Cre recombinase expression to generate a comprehensive lysosomal protein map covering major brain cell types, including neurons, astrocytes, oligodendrocytes, and microglia [8][11] - The study highlights the impact of SLC45A1 on the stability of the V-ATPase complex on lysosomal membranes, linking its deficiency to impaired lysosomal acidification and mitochondrial dysfunction [4][8][16] Implications for Future Research - This research lays the groundwork for future studies on lysosomal biology and its role in neurodegenerative diseases, emphasizing the need to explore the specific functions of different lysosomal proteins in various brain cell types [11]

Core Findings - A new study indicates that weakened or irregular circadian rhythms in older adults may increase the risk of dementia, as published in the journal Neurology [1][2] - Circadian rhythms regulate various physiological processes, and their disruption can lead to health issues, potentially serving as a risk factor for neurodegenerative diseases like dementia [1] Study Details - The research involved 2,183 participants with an average age of 79, all of whom were dementia-free at the start of the study [1] - Participants wore monitoring devices for an average of 12 days to assess the strength and regularity of their circadian rhythms, categorized into high, medium, and low amplitude groups [1] Follow-Up Results - Over an average follow-up period of 3 years, 176 participants were diagnosed with dementia, approximately 8% of the total [2] - Among the high amplitude group of 728 individuals, 31 developed dementia, while 106 out of 727 in the low amplitude group were diagnosed [2] - After adjusting for factors such as age, blood pressure, and heart disease, the risk of dementia in the low amplitude group was found to be 2.5 times higher than that in the high amplitude group [2]

Core Viewpoint - GLP-1 class drugs, including semaglutide and tirzepatide, show potential in treating not only type 2 diabetes and obesity but also various neurological and psychiatric disorders, supported by emerging clinical data [1][2][6]. Group 1: Mechanism and Applications - GLP-1 drugs activate GLP-1 receptors to enhance insulin secretion, suppress glucagon secretion, slow gastric emptying, and reduce appetite, leading to weight loss [1]. - These drugs have been approved for treating type 2 diabetes, obesity, cardiovascular diseases, kidney diseases, and metabolic liver diseases [1]. - Recent studies indicate that GLP-1 drugs may have therapeutic benefits for neurodegenerative diseases, substance use disorders, and other neurological conditions [2][3][6]. Group 2: Clinical Evidence and Safety - A review of clinical evidence highlights the potential of GLP-1 drugs in treating Parkinson's disease and Alzheimer's disease, with a focus on their neuroprotective properties [6][7]. - There is increasing evidence that GLP-1 drugs may reduce addictive behaviors in individuals with substance use disorders [6]. - Most patients with neuropsychiatric disorders using GLP-1 drugs have shown acceptable safety profiles, although large-scale confirmatory trials are still lacking [6][13]. Group 3: Future Research Directions - The role of GLP-1 drugs in neurological conditions will continue to evolve as new clinical trial data emerges, providing clearer evidence of their potential uses and limitations [13]. - Despite enthusiasm for GLP-1 drugs in treating central nervous system diseases, no large-scale trials have yet confirmed their efficacy and safety in these areas [13].

Core Viewpoint - The article discusses the increasing interest and cautious use of GLP-1 medications for weight management in the elderly population, highlighting both potential benefits and necessary precautions in their application [4][8][12]. Group 1: GLP-1 Medications in Elderly Care - GLP-1 medications have gained popularity among patients aged 65 and older, with many seeking these treatments for obesity management [4]. - The CDC reports that nearly 40% of individuals aged 60 and above are classified as obese, which significantly impacts their health and quality of life [5]. - Experts emphasize the need for careful evaluation of elderly patients before prescribing GLP-1 medications, particularly for those with frailty or cognitive impairments [8][12]. Group 2: Broader Implications of GLP-1 Medications - Recent studies suggest that GLP-1 medications may have effects beyond glucose control and weight loss, potentially influencing cardiovascular health, addiction behaviors, certain cancers, and cognitive function [6][11]. - In the context of neurodegenerative diseases, GLP-1 medications may help slow cognitive decline due to their anti-inflammatory properties and ability to improve insulin signaling [11]. - Research indicates that patients using GLP-1 receptor agonists have lower all-cause mortality rates compared to those on other diabetes treatments, although the relationship with different cancer types remains unclear [11]. Group 3: Clinical Considerations and Future Research - The complexity of medication decisions for elderly patients necessitates a comprehensive assessment of their overall health, including potential side effects and interactions with other medications [12]. - Experts advocate for a gradual approach to GLP-1 treatment, focusing on maintaining strength, independence, and quality of life rather than solely on weight loss [12]. - There is a recognized need for more representative clinical trial data for older populations, as current studies show that older patients may experience higher rates of discontinuation due to gastrointestinal side effects [12].

Group 1 - The article discusses the advancements in research on Amyotrophic Lateral Sclerosis (ALS) led by Don Cleveland, highlighting his contributions to understanding the disease's mechanisms and developing new therapies [2][3] - Cleveland emphasizes the importance of perseverance in scientific research, stating that intelligence and experimental skills are not the only keys to success; rather, persistence is essential [2][4] - The article mentions the potential of Antisense Oligonucleotide (ASO) therapy in treating genetic forms of ALS, with Cleveland noting that some progress has been made in reversing symptoms, although results are still not ideal [5][6] Group 2 - Cleveland expresses skepticism about the immediate impact of artificial intelligence (AI) in his field, acknowledging its potential but stressing the need for patience in drug testing and development [6][8] - He highlights the importance of rigorous clinical trials, stating that the effectiveness of ALS therapies can only be determined through long-term results [6][7] - The article reflects Cleveland's belief in the international nature of science, advocating for collaboration and competition to drive scientific progress, and noting China's significant investment in research [8][9]